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NNRTI polymorphisms and response to NNRTI-based ART

NNRTI polymorphisms and response to NNRTI-based ART. Lucy Garvey, Linda Harrison, Peter Tilston, Andrew Phillips, Caroline Sabin, Anna Maria Geretti, David Dunn, Nicola Mackie. Background Polymorphisms occur at codons within regions 90-108, 179-190 and 225-348 in ARV-naive individuals

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NNRTI polymorphisms and response to NNRTI-based ART

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  1. NNRTI polymorphisms and response to NNRTI-based ART Lucy Garvey, Linda Harrison, Peter Tilston, Andrew Phillips, Caroline Sabin, Anna Maria Geretti, David Dunn, Nicola Mackie

  2. Background Polymorphisms occur at codons within regions 90-108, 179-190 and 225-348 in ARV-naive individuals Although some confer low-level resistance to NNRTIs in vitro, their impact on virological response remains unclear Aims 1. To determine the prevalence of polymorphisms at the following codons* in ARV-naive subjects: 2. To assess their impact on early virological response to NNRTI-based therapy * IAS Dec 2008 and Stanford database http://hivdb.stanford.edu accessed 07 Jan 2010

  3. Population ARV-naive patients starting NNRTI-based Rx with WT or polymorphisms only on baseline genotype (any major RT mutation excluded) Analysis Assess early virological response at week 4 (approx timing wk 2-6): WT versus any polymorphism WT versus individual codon (irrespective of amino acid mutation) Results to date 2235 eligible subjects 1221 (55%) at least one polymorphism Most frequently seen at codons 135 (39%), 179 (10%), 98 (8%) Average 2.4 log10drop by wk 4

  4. n=35 238 n=217 179 n=79 138 n=877 135 n=51 106 Polymorphism 103 n=35 101 n=39 n=176 98 n=71 90 -.5 -.25 0 .25 .5 Average effect on reduction in viral load at week 4 Difference in reduction in viral load at week 4

  5. Proposed Further Analysis Details on demographics including: calendar year, first-line ARV details (EFV or NVP), HIV subtype Assess time to VL<50 copies/mL: WT versus any polymorphism WT versus individual codon Look at number of polymorphisms per patient

  6. Prevalence of PI mutations in HIV-infected UK adults treated with ritonavir-boosted lopinavir as their first PI Tristan Barber, David Dunn, Linda Harrison, Loveleen Bansi, Ian Williams, Deenan Pillay

  7. Background • Little is known about the clinical significance of PI mutations for successful sequencing of PIs • The Quest laboratory database reported a novel LPV resistance pathway with L76V1 • Looked at data from the UK HIV Drug Resistance Database linked to the UK CHIC study for: • patients failing LPV/r containing ART with demonstrable resistance • the prevalence of L76V • other novel resistance mutations 1Nijhuis, et al. Failure of treatment with first line lopinavir boosted with ritonavir can be explained by novel resistance pathways with protease mutation 76V. JID 2009; 200: 698-709.

  8. Methods Population • PI naïve adults, starting LPV/r as their first PI Virological failure • viral load >400 c/ml after previously being <400 • OR viral load >400 c/ml for the first 6 months of LPV/r • Patients were censored if they stopped LPV/r or started another PI Resistance • For those failing, we looked for resistance tests • Resistance was defined as ≥1 major PI mutation on the IAS list (Dec 2008)

  9. Results • N = 3056 • Previous ART:1580 (52%) naïve 569 (19%) NNRTI HAART 907 (30%) other • 811 (27%) rebounded:370 (23%) naïve139 (24%) NNRTI HAART302 (33%) other

  10. Resistance • Of 811 rebounding: 291 (36%) had resistance tests • Of 291 with tests:32 (11%) had PI resistance • 3 had L76V V82A 5 Q58E 3 M46L I84V 2 M46L V82A 2 L90M 2 L33F M46L V82A I84V L90M 1 V32I M46I I47A/V V82A 1 L33F M46L V82A L90M 1 M46L V82T I84V L90M 1 V32I M46I I47A 1 M46I L76V I84V 1 M46I V82A V82S 1 M46I L76V 1 M46I I84V 1 M46L T74P 1 L33F 1 M46I 1 M46I/L 1 M46L 1 I47V 1 L76V 1 V82T 1 I84V 1

  11. Outcomes of 2nd line ART: 1st line NNRTI to 2nd line PI/r Laura Waters, David Asboe, Anton Pozniak, Loveleen Bansi, Chloe Orkin, Erasmus Smit, Esther Fearnhill & Andrew Phillips. UK Resistance Database and UK CHIC Study

  12. Background • A combination of 2 NRTI + 1 NNRTI is the most common first line regimen worldwide • Treatment failures continue to occur • Second line regimens are usually PI/r based and should include at least 2 active agents1 • Unclear how many active NRTI are necessary with 2nd line PI/r based therapy 1) 2008 BHIVA Guidelines

  13. Objectives • To identify factors associated with failing 2nd line, ritonavir boosted PI-based ART • To investigate the importance of the number of new or fully active NRTI started at 2nd line

  14. Methods 1 • Eligibility Patients failing first line NNRTI-ART (VL >200 copies/ml after 4 months) and starting PI/r for the first time • Exclusions • VL<200 copies/ml at start of 2nd line • <4 months follow up • failed new NRTI between first and second-line therapy

  15. Methods 2 • Virological failure of 2nd line ART was defined as VL>200 copies/ml despite 4 months continuous use • NRTI GSS calculated for 2nd line regimens using Stanford • Statistical Analyses: • Kaplan-Meier: time to failing 2nd line HAART • Logistic regression: identify factors associated with having a resistance test • Cox regression: identify factors associated with failing 2nd line HAART

  16. Patients starting new drugs 2nd line (n = 1103) Started non-PI/r regimen 2nd line (n = 502) Started PI/r Regimen 2nd line (n = 601) Unboosted PI 45 New NNRTI 138 New NRTI only 318 Other 1 Excluded HIV-RNA <200 at 2nd line 100 <4 months follow-up 56 Failed new NRTI between 1st and 2nd line 42 Eligible for Study (n = 403)

  17. Time to failing 2nd line HAART 222/403 (55.1%) experienced virological failure of 2nd line

  18. Independent factors associated with failure of 2nd line HAART (N=403) 1 HR=1.00 (0.82, 1.21), p=0.99 if fitted as a continuous variable

  19. GSS amongst those who had a resistance test performed (N=211) Patients not receiving any NRTIs (N=5) excluded 1 Chi-squared test

  20. Independent factors associated with failure of 2nd line HAART (N=211) 1 HR=1.14 (0.76, 1.72), p=0.51 if fitted as a continuous variable

  21. Summary • Of 403 patients who started 2nd line PI/r, 216 (54%) patients had a resistance test performed after failing 1st line HAART • NRTI GSS was >2 for 50% of patients with resistance tests performed • Neither NRTI GSS nor the number of new NRTI started at 2nd line were associated with virological failure of 2nd line HAART

  22. Conclusions • Among patients who have failed an NNRTI 1st line then started a PI/r 2nd line there was extensive variability in the number of new NRTI started, hence in the predicted activity of the NRTI backbone • We found little evidence that: • number of new NRTI started • predicted NRTI activity within the regimen, were associated with risk of virologic failure of the 2nd line regimen

  23. Conclusions • These findings may reflect: • the strong potency of the PI/r component and/or • a negative impact of initiating more new agents in terms of tolerability and/or adherence • However, further analyses are required to more extensively explore this lack of association before drawing firm conclusions

  24. Prevalence and patterns of Raltegravir resistance in treated patients in Europe- CORONET Study. CORONET European collaborative study in area of integrase resistance repository of integrase sequences from 9 European centres and 2 multi-centre repositories (UK Drug Resistance database/ EuResist database). AIM - To survey patients experiencing virological failure on Raltegravir (RAL) based regimen within CORONET, and to assess the influence of HIV-1 subtype on patterns of RAL genotypic resistance that emerge. Study Group Integrase sequences available for: 255 patients- viraemic on RAL- based therapy plus 591 patients- prior to starting RAL- based therapy. - Analysis included major INI resistance-associated mutations (T66I, E92Q, F121Y, G140A/S, Y143R/C,S147G, Q148H/R/K and N155H) other non-classic mutations at the same codons and mutations implicated in INI resistance in vivo or in vitro (codons 51, 54, 68, 74, 95, 97, 114, 125, 128, 138, 145, 146, 151, 153, 154, 157, 160, 163, 203, 230, 263).

  25. Distribution of HIV-1 subtypes among INI experienced and naïve patients. Treatment naive Treatment experienced

  26. Prevalence and patterns of major Raltegravir Associated Mutations (RAMs) in INI-experienced patients (n=255). Table 1: Prevalence of major integrase inhibitor RAMs in INI experienced patients. Table 2: Patterns of major integrase inhibitor RAMs in INI experienced patients.

  27. Non-classic mutations at major INI resistance codons detected in INI-experienced patients (n=255).

  28. Prevalence of other mutations implicated in INI- resistance among INI experienced patients n=255. *P value< 0.0001 vs. INI- naive patients. (Fisher’s exact test)

  29. Novel mutations associated with INI experience. *P values by Fisher’s exact test

  30. Conclusions. • 55.3% of viraemic patients on RAL lacked major INI resistance-associated mutations- overall, 114/255 (44.7%) RAL experienced patients had ≥1 major INI RAMs. • Of 3 major recognised pathways of genotypic resistance to RAL : N155H and Y143R/C occurred in both B and non- B HIV1 subtypes. Q148H/R/K- significantly more prevalent in subtype B. • Q148 was highly conserved among INI naive patients infected with either subtype B or non-B virus in contrast with INI experienced counterpart. • T97A, E138D/K and V151I significantly more common in RAL experienced patients.

  31. Conclusions. • Identified 3 novel mutations that were more prevalent in RAL experienced patients in comparison with RAL drug naive: K159Q/R, I161L/M/N/T/V and E170AG. • K159Q/R observed in subtype B only- in 1 patient with major INI RAMs and in 3 other patients with other INI associated mutations. • I161L/M/N/T/V seen in subtype B and CRFO2- in 1 patient with major INI RAMs and in 5 patients with other mutations implicated in INI resistance. • E170AG seen in subtype B viruses in 2 patients alongside 2 major INI RAMs and in all patients with other INI associated resistance mutations. • Require further clarification of their impact across subtype on drug susceptibility to 1st and 2nd generation INIs.

  32. Comparison of subtypes B and C accessory mutations observed in high level NRTI resistance Codon 43 Codon 118 Statistically significant differences (p<0.001) between subtype B and C in detection of mutants at codons 43 and 118 with accumulation of TAMS. Impact of 43, 44, and 118 on resistance and fitness in subtype B and C backgrounds now being analysed in phenotypic assays (Tamyo Mbisa).

  33. PLATO II Project of COHERE: Analysis of predictors of triple class virologic failure (TCVF) and outcomes for patients with TCVF. Results so far relating to resistance (EACS Cologne, manuscript drafted) 722 patients who developed TCVF and for whom at least one resistance test was available at some point up to time of TCVF (1514 tests). 444 / 618 (72%) patients with a resistance test while on an NRTI after NRTI failure had an NRTI mutation. 372 / 427 (87%) patients with a resistance test while still on an NNRTI after NNRTI failure had an NNRTI mutation. 65 / 240 (27%) patients with a resistance test while on a PI after failing a PI/r had a PI mutation. Risk factors for PI resistance: longer time on a PI/r regimen since PI/r failure, being treated with an NNRTI-containing regimen, and for having previously used a greater number of PIs.

  34. In the second round of the project (in progress) we will expand the scope of the resistance data pooled to include all resistance tests performed in people with TCF, including those tests performed beyond the time of TCF.

  35. The specific aims in the second round will be in people with TCVF: • To assess the proportion of people with TCVF for whom resistance mutations to the three original classes, and to the newer drug classes, are documented, either up to the time of TCVF or beyond. • To document calendar time trends in the GSS for people on ART. The GSS at any calendar time point will be based on cumulative resistance tests up to that point (and so could be calculated for those with VL < 50 as well as for those with higher VL). • In people on ART, to assess the extent to which the documented increasing trend over calendar time in proportion of people with VL < 50 is explained statistically by the current GSS (i.e. the extent to which the rate ratio for the effect of calendar time on VL < 50 moves to 1 after adjustment for the current GSS).

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